The noradrenergic locus coeruleus (LC) is enriched with opioid receptors and has been a useful model to study the neuronal mechanisms of opioid action. Recently, we found a novel effect of morphine, a classic opioid drug, on the firing pattern of LC neurons. Our electrophysiological studies show that a single dose of morphine induces long-lasting synchronous oscillatory discharges in the LC in addition to its well-known inhibitory effect (Zhu and Zhou, 2001). This morphine-induced synchronous activity in the LC may have important implications in the development of opioid addiction. As a result of the synchronized LC firing, morphine may facilitate the release of neurotransmitter norepinephrine (NE) in widespread brain areas that receive noradrenergic LC input. NE, an important neuromodulator, has been shown to induce and facilitate synaptic plasticity in several brain regions. We propose that the morphine-induced synchronous activity in the LC is an important neuronal signal that induces synaptic plasticity in critical target areas, which are known to contribute to opioid addiction. This application will more thoroughly study the morphine-induced synchronous activity in the LC and its influence on the LC target areas. A unique strength of this application is that we employ a multiple-electrode recording technique that allows us to record several neurons simultaneously so that the temporal relationship among the activities of LC neurons can be studied.
Three specific aims are proposed.
Specific Aim 1 will further characterize the morphine-induced synchronous oscillatory discharges in the LC in an in vivo rat model. Effects of acute and repeated administration of morphine on synchronous activity in the LC will be examined.
Specific Aim 2 will identify the specific mechanisms underlying the morphine-induced synchronous activity in the LC. We will examine the role of electrotonic coupling among LC neurons and the role of excitatory synaptic input in the morphine-induced LC synchrony.
Specific aim 3 will study the role of LC input in the morphine-induced synaptic plasticity in the dentate gyrus of the hippocampus, an LC target area thought to be involved in opioid addiction. These experiments will improve our understanding of neuronal mechanisms of opioid action, which is crucial for understanding and perhaps treating of opioid addiction.
|Zhu, Hong; Zhou, Wu (2010) Discharge activities of neurons in the nucleus paragigantocellularis during the development of morphine tolerance and dependence: a single unit study in chronically implanted rats. Eur J Pharmacol 636:65-72|
|Zhu, Hong; Jordan, James R; Hardy, Steven P G et al. (2007) Linear acceleration-evoked cardiovascular responses in awake rats. J Appl Physiol 103:646-54|